Among patients with human papillomavirus–positive oropharyngeal cancer (HPV-OPC), persistence of HPV following treatment is associated with a poorer prognosis.
Results of a new study show that the persistence of HPV16 DNA, detected in oral rinses after treatment has ended, may be predictive of disease recurrence.
In a cohort of 124 patients with HPV-OPC, HPV16 DNA was detected in oral rinses from 54% (n = 67) of patients at the time of their diagnosis. Following treatment, it was detected in only six patients after treatment, including five patients with persistent oral HPV16 DNA that was also detected at diagnosis.
All five patients with persistent HPV16 experienced disease recurrence, with three eventually dying of their cancer. Conversely, only nine of 119 patients without persistent oral HPV16 DNA developed recurrent disease.
“Our findings indicate that persistent HPV16 DNA in oral rinses may be a useful early marker of disease that has either recurred or never fully responded to treatment,” said first author Eleni Rettig, MD, of the Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
“In the clinical setting, this could one day be a part of routine surveillance after treatment for HPV-positive oropharyngeal cancers, in addition to clinical examination and imaging,” she told Medscape Medical News.
The study was published online July 30 in JAMA Oncology.
In an accompanying editorial, Julie E. Bauman, MD, MPH, and Robert L. Ferris, MD, PhD, both of the University of Pittsburgh, in Pennsylvania, point out that HPV-specific biomarkers in oropharyngeal squamous cell carcinoma (OSCC) may be used to improve clinical outcomes, and “this pioneering study demonstrates an association between persistent oral HPV16 DNA detection and recurrence.”
But an ideal biomarker for recurrence, they say, should have a number of characteristics, including high sensitivity to identify the population with salvageable locoregional recurrence, a high positive predictive value (PPV) so as to avoid the economic, physical, and emotional costs of false-positive evaluations, and accuracy for detecting subclinical locoregional recurrence.
The prevalence of a positive oral rinse at diagnosis, however, was only 54%, and so the “low sensitivity of the assay, even with gross disease present, raises legitimate questions regarding its utility for diagnosing subclinical disease,” they say.
Of the six cases in which posttreatment HPV16 DNA was detected, five patients developed recurrent disease, representing a PPV of 83%, the editorialists write. When restricted to the five cases with persistent HPV16 DNA, the PPV then becomes 100%.
Although this looks impressive, they point out that “persistence can only occur in those who initially test positive — making this recurrence biomarker irrelevant for half of patients with HPV-positive” disease.
In addition, they add, the PPV can apply to any recurrence, including presentation with distant metastases, and “unfortunately, early diagnosis of disseminated OPSCC [oropharyneal squamous cell carcinoma] has not been associated with improved survival.”
“Operating characteristics, including low sensitivity, low confidence in the PPV, and high NNT [number needed to treat], preclude immediate clinical adoption,” say Dr Bauman and Dr Ferris flagyl online. They add that incorporating an HPV-specific biomarker in future surveillance guidelines will require some refinement, including improved sensitivity and perhaps combining it with other serologic markers, such as HPV16 DNA or E6 antibodies.
“Meanwhile, the high negative predictive value of oral rinse HPV16 DNA detection raises the promise of deintensifying surveillance visits and/or costly imaging, particularly if on a prospective trial,” they conclude.
Dr Rettig agrees that more studies are needed before this test can be recommended. “For example, we need to understand when and how frequently to administer the test, what exactly we should do with a positive result, and what the cost-effectiveness would be, given the small number of individuals who actually have persistent oral HPV16 ― only five of 124 people in our study,” she said.
“We also can’t say for sure that all of the HPV16 DNA comes from tumor cells, and in some cases, it might just come from an oral HPV16 infection,” Dr Rettig explained. “For all of these reasons, right now, this test should only be used in the research setting until we have more information from additional studies.”
Associated With Recurrence
In this study, Dr D’Souza and colleagues examined HPV DNA detection in oral rinses after treatment for HPV-OPC and how it related to disease recurrence and survival.
This prospective cohort study included HPV-OPC patients diagnosed from 2009 to 2013 at four centers. Oral rinse samples were collected at diagnosis and after treatment (9, 12, 18, and 24 months after diagnosis) and were evaluated for HPV DNA. One or more posttreatment oral rinses were available for the 124 patients included in the study.
The median follow-up time was 33 (24-41) months, during which there were 14 recurrences and six deaths — all due to recurrent disease.
Two years after diagnosis, disease-free survival (DFS) was 92% (95% confidence interval [CI], 94% – 100%), and overall survival was 98% (95% CI, 93% – 99%).
The presence of HPV16 DNA in oral rinses at the time of diagnosis was not associated with either DFS (P = .15) or overall survival (P = .14), but on univariate analysis, persistent HPV16 DNA detection in oral rinses (eg, both at diagnosis and any time after treatment) was associated with a greater than 20-fold increased risk for recurrence (hazard ratio [HR], 29.7; 95% CI, 9.0 – 98.2) and death (HR, 23.5; 95% CI, 4.7 – 116.9).
It still remained associated with both DFS (adjusted HR [aHR], 35.8; 95% CI, 8.6 – 149.1) and overall survival (aHR, 16.1; 95% CI, 2.8 – 92.7) after adjusting for pack-years of smoking and tumor stage.
This research was supported financially by the Johns Hopkins Richard Gelb Cancer Prevention Award (Dr D’Souza), the Oral Cancer Foundation (Dr D’Souza), the National Institute of Dental and Craniofacial Research, and the National Institutes of Health Training in Otolaryngology grant (Dr Rettig). Several of the authors report relationships with industry, as noted in the article. The editorialists report no relevant financial relationships.
*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.